Synthesis of conjugated enediynes via palladium catalyzed cross-coupling reactions of potassium alkynyltrifluoroborates George W. Kabalka, * Gang Dong and Bollu Venkataiah Departments of Chemistry and Radiology, The University of Tennessee, Knoxville, TN 37996-1600, USA Accepted 6 December 2004 Available online 21 December 2004 Abstract—An efficient synthesis of cross-conjugated enediynes has been developed utilizing the palladium catalyzed cross-coupling reactions of 1,1-dibromo-1-alkenes with potassium alkynyltrifluoroborates under mild conditions. Ó 2004 Elsevier Ltd. All rights reserved. Cross-conjugated enediynes have recently received con- siderable attention due to their extensive applications in non-linear optics (NLO), 1 macrocyclic ligands, 2 opti- cal switches, 3 and the synthesis of polycyclic aromatic hydrocarbons (PAHs). 4 Preparative methods for enedi- ynes are limited. The Sonogashira reaction can be uti- lized 5 as well as the palladium catalyzed coupling reac- tion of ketene butyltelluroacetals with alkynes. 6 The Sonogashira reaction normally produces a mixture of bromoenyne, enediyne, and recovered starting di- bromoalkene. 5e,7 In some cases the yields are low. 5c,d The butyltelluroacetal method involves the use of vinylic telluride compounds that are toxic and often difficult to prepare. Thus, the development of a simple and efficient approach to cross-conjugated enediynes is of great interest. During the past 20 years, Suzuki-Miyaura cross-cou- pling reactions have provided preparative methods for effectively creating carbon–carbon bonds. The coupling reactions of aryl-, alkyl-, and alkenylboron compounds (including boronate esters, boranes, and boronic acids) have been investigated extensively. 8 However, the cou- pling of alkynylboron compounds has been limited to B-alkynyl-9-BBN borate complexes, 9 alkynyltrialkoxy- borate complexes, 10 and lithium 1-alkynyl(triisoprop- oxy)borates. 11 Because alkynylboronic esters are stronger Lewis acids than aryl- and alkenylboronate esters and are easily hydrolyzed, 12 their use in organic reactions can be problematic. Recently the use of potas- sium alkynyltrifluoroborates in carbon–carbon bond forming reactions has attracted significant attention due to their stability and accessibility. 13 In connection with our ongoing studies of cross-coupling reactions using potassium organotrifluoroborates, 14 we developed an efficient synthesis of cross-conjugated mono-enedi- ynes using the cross-coupling of potassium alkynyltrifluo- roborates with 1,1-dibromo-1-alkenes. Herein, we wish to disclose the results of this study. Various palladium catalysts, solvents, and reaction con- ditions were examined using (2,2-dibromovinyl)-benz- ene, 1, and potassium (p-tolylethynyl)trifluoroborate, 2, as model substrates (Table 1). 1 (1 equiv) was treated with 2 (2 equiv) in the presence of 5 mol % of Pd(dppf)Cl 2 /Cs 2 CO 3 (3 equiv) at 50 °C in methanol (Ta- ble 1, entry 1). Under these conditions, the reaction was sluggish. Fifty-two percent of the starting material, 1, was recovered after 12 h. The corresponding enediyne 3 was obtained in 10% yield, and 1,3-diyne 4 was isolated as the major product in 36% yield. The homo- coupling product of 1,1-dibromo-1-alkene and mono- substituted bromoenyne were not detected although they are commonly reported as byproducts in Sonogash- ira reactions. 5,6 Using DMF and toluene as solvents, the isolated yields of enediyne 3 were 21% and 18%, respec- tively (Table 1, entries 2 and 3). When THF was used as solvent, the yield of 3 increased to 43% and only 26% of starting material 1 was recovered (Table 2, entry 4). The addition of a small amount of water increased the yield of 3 to 52% as well as decreased the reaction time to 4 h (Table 1, entry 5). 15 As the reaction proceeds, the mix- ture becomes black. Gas chromatographic analysis of the black reaction mixture (presumably due to metallic 0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved. doi:10.1016/j.tetlet.2004.12.021 Keywords: Enediynes; Trifluoroborate; Cross-coupling; Palladium catalyzed. * Corresponding author. Tel.: +865 974 3260; fax: +865 974 2997; e-mail: kabalka@utk.edu Tetrahedron Letters 46 (2005) 763–765 Tetrahedron Letters